The authors have declared that no competing interests exist.
Conceived and designed the experiments: ZX HL DL. Analyzed the data: ZX DL. Wrote the paper: DL JL WZ JR LY HL ZX. Performed article search: HL DL. Conducted analyzed data: ZX DL.
The hypoxia-inducible factor-1 alpha (HIF1A) plays a vital role in cancer initiation and progression. Previous studies have reported the existence of HIF1A P582S and A588T missense polymorphisms in renal, urothelial and prostatic carcinomas, however the effects remain conflicting. Therefore, we performed a meta-analysis to assess the association between these sites and the susceptibility of urinary cancers.
We searched the PubMed database without limits on language until Nov 25, 2012 for studies exploring the relationship of HIF1A P582S and A588T polymorphisms and urinary cancers. Still, article search was supplemented by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of the associations between the two by RevMan 5.0 software. Simultaneously, publication bias was estimated by funnel plot and Begg’s test with Stata 12.1 software.
Overall, 11 individual case-control studies with 5195 cases and 5786 controls for P582S polymorphism, and 9 studies with 3482 cases and 4304 controls for A588T polymorphism were respectively included in the final meta-analysis. For HIF1A P582S polymorphism, individuals with TT genotype showed 1.60 fold higher risk than the others carrying CT or CC genotypes in Caucasian population (OR = 1.60, 95% CI = 1.09–2.33,
The current findings suggest that HIF1A P582S polymorphism correlates with urinary cancers risk in Caucasian population, while A588T polymorphism may increase the risk of urinary cancers in Asian population and prostate cancer.
Cancer, known as a malignant neoplasm, is involving in unregulated cell growth. Approximately 12.7 million cancers were newly diagnosed and 7.6 million people died of cancer worldwide
Hypoxia refers to low oxygen condition and is common in solid tumors
The inconsistent conclusions may have resulted from differences in patient ethnic backgrounds and relatively small sample sizes. In this study, we collected and summarized published case-control studies on the two most widely studied polymorphisms in urinary cancers to shed light on current uncertain claims.
In current meta-analysis, the database of PubMed was scrutinized without limits on language until Nov 25th, 2012. Epidemiologic studies exploring the relationship of HIF1A P582S and/or A588T polymorphisms and urinary cancers were identified. The following keywords were adopted: (hypoxia-inducible factor-1 OR hypoxia-inducible factor OR HIF-1 OR HIF1A OR HIF) and (polymorphism OR variant OR SNP OR mutation) and (kidney OR renal OR urothelial OR transitional cell carcinoma OR bladder OR prostatic OR prostate). Meanwhile, the references of eligible studies were manually screened for potential case-control studies. Finally, a total of 248 abstracts meeting the search criteria were retrieved. The eligibility criteria of the meta-analysis were: (a) The studies had to be case-control studies exploring the associations between HIF1A P582S and/or A588T polymorphisms and urinary cancers; (b) The studies provided the number of cases and controls for various genotypes. The exclusion criteria of the meta-analysis were: (a) animal studies; (b) reviews, editorial, comments; (c) studies with duplicate data. On screening titles, abstracts and full texts, 11 eligible studies conformed to inclusion criteria were finally included.
For each study, we extracted data through a standard form. The following characteristics were respectively extracted from the included studies: name of first author, year of publications, country of origin, ethnicity, gender of recruited subjects, cancer types, numbers of various genotypes in case and control groups, methods for detecting HIF1A P582S and/or A588T polymorphisms, Hardy-Weinberg equilibrium (HWE). In the case of disagreement, discrepancies of included studies were resolved by discussion.
The genotypes and alleles difference of HIF1A P582S and A588T polymorphisms in Caucasian and Asian populations was calculated by chi-square test. HWE for HIF1A P582S and A588T polymorphisms of control groups was extracted from the original studies. In case of studies without reporting HWE status, HWE in control group was calculated by the chi-square test. And a
Overall, a total of 248 abstracts meeting the search criteria were retrieved through PubMed. After screening titles, abstracts and full texts, we identified 11 qualified case-control studies exploring the relationship of HIF1A P582S and/or A588T polymorphisms and urinary cancers. The flow diagram of search strategy in this meta-analysis was shown in
First Author | Year | Ref. | Country | Ethnicity | Gender | Cancer Types | SNPSites | Cases, n | Controls, n | Genotyping methods | HWE | ||||
WW | WM | MM | WW | WM | MM | Y/N | |||||||||
Li P | 2012 | 12 | China | Asian | M | Prostate | P582S | 612 | 48 | 2 | 659 | 57 | 0 | Taqman | Y |
A588T | 614 | 47 | 1 | 685 | 31 | 0 | Taqman | Y | |||||||
Qin C | 2012 | 13 | China | Asian | M/F | Renal | P582S | 572 | 46 | 2 | 578 | 43 | 2 | Taqman | Y |
A588T | 575 | 45 | 0 | 584 | 39 | 0 | Taqman | Y | |||||||
Foley R | 2009 | 14 | Ireland | Caucasian | M | Prostate | P582S | 65 | 30 | 0 | 175 | 13 | 0 | Sequencing | Y |
Morris MR | 2009 | 15 | Poland | Caucasian | M/F | Renal | P582S | 290 | 39 | 3 | 262 | 46 | 5 | Taqman | Y |
A588T | 313 | 10 | 2 | 294 | 15 | 0 | Taqman | Y | |||||||
Jacobs EJ | 2008 | 16 | USA | Mixed | M | Prostate | P582S | 1156 | 252 | 12 | 1138 | 284 | 28 | Taqman | N |
Nadaoka J | 2008 | 17 | Japan | Asian | M/F | Bladder | P582S | 197 | 21 | 1 | 419 | 42 | 0 | PCR-RFLP | Y |
A588T | 204 | 13 | 2 | 421 | 40 |
PCR-RFLP | Y | ||||||||
Orr-Urtreger A | 2007 | 19 | Israel | Caucasian | M | Prostate | P582S | 287 | 99 | 16 | 217 | 80 | 3 | PCR-RFLP | Y |
A588T | 198 | 2 | 0 | 298 | 2 | 0 | PCR-RFLP | Y | |||||||
Li H | 2007 | 18 | USA | Mixed | M | Prostate | P582S | 818 | 209 | 14 | 995 | 221 | 18 | PCR-RFLP | Y |
A588T | 1053 | 13 | 0 | 1247 | 17 | 0 | PCR-RFLP | Y | |||||||
Chau CH | 2005 | 20 | USA | Mixed | M | Prostate | P582S | 161 | 29 | 6 | 179 | 14 | 3 | Sequencing | N |
A588T | 195 | 1 | 0 | 196 | 0 | 0 | Sequencing | – | |||||||
Ollerenshaw M | 2004 | 21 | UK | Caucasian | M/F | Renal | P582S | 16 | 54 | 90 | 1 | 90 | 71 | PCR-RFLP | N |
A588T | 65 | 67 | 14 | 239 | 39 | 10 | PCR-RFLP | N | |||||||
Clifford SC | 2001 | 11 | UK | Caucasian | M/F | Renal | P582S | 42 | 6 | 0 | 110 | 27 | 6 | PCR-SSCP | N |
A588T | 47 | 1 | 0 | 140 | 4 | 0 | Sequencing | Y |
W: wild type alleles (1772C or 1790G);
M: mutant type alleles (1772T or 1790A);
HWE: Hardy-Weinberg Equilibrium;
Frequency of genotypes “AA+AG”.
As for HIF1A P582S polymorphism, 1106 controls of Caucasian population and 1803 controls of Asian population were included in the meta-analysis. The frequencies of the C and T alleles for Caucasian were 80.74%, 19.26%, while those for Asian were 95.90% and 4.10%, respectively (
SNPs | Genotype/Allele | Caucasian | Asian | ||||
n | % | n | % | ||||
P582S | Genotypes | CC | 765 | 69.17 | 1657 | 91.90 | |
CT | 256 | 23.15 | 144 | 7.99 | |||
TT | 85 | 7.69 | 2 | 0.11 | 0.000 |
||
TT+CT | 341 | 30.83 | 146 | 8.10 | 0.000 |
||
Alleles | C | 1786 | 80.74 | 3458 | 95.90 | ||
T | 426 | 19.26 | 148 | 4.10 | 0.000 |
||
A588T | Genotypes | GG | 971 | 93.28 | 1690 | 93.89 | |
AA+AG | 70 | 6.72 | 110 | 6.11 | 0.518 |
||
Alleles |
G | 2002 | 96.16 | 2608 | 97.39 | ||
A | 80 | 3.84 | 70 | 2.61 | 0.016 |
Study by Nadaoka J was not included;
As for HIF1A A588T polymorphism, The frequencies of the AA+AG and GG genotypes for Caucasian were 6.72%, 93.28% respectively, while those for Asian were 6.11% and 93.89%. The frequency distributions of the genotypes for HIF1A A588T polymorphism were statistically insignificant between the Caucasian and Asian groups. The frequencies of the A and G alleles for Caucasian were 3.84%, 96.16%, while those for Asian were 2.61% and 97.39%, respectively (
The main results of meta-analysis about HIF1A P582S polymorphism were shown in
Genetic Model | Groups/Subgroups | Studies, n | Heterogeneity Test | Statistical Model | Test for Overall Effect | |||
OR | 95% CI | |||||||
TT vs CT+CC | Overall | 11 | 55 | 0.02 | Random | 1.17 | 0.67–2.05 | 0.57 |
Overall in HWE | 7 | 33 | 0.19 | Fixed | 1.38 | 0.85–2.26 | 0.19 | |
Caucasian | 5 | 51 | 0.11 | Fixed | 1.60 | 1.09–2.33 | ||
Caucasian in HWE | 3 | 76 | 0.04 | Random | 1.57 | 0.22–11.14 | 0.65 | |
Asian | 3 | 0 | 0.50 | Fixed | 2.38 | 0.60–9.39 | 0.22 | |
Prostate | 6 | 69 | 0.01 | Random | 1.31 | 0.54–3.20 | 0.55 | |
Prostate in HWE | 4 | 61 | 0.08 | Random | 2.03 | 0.58–7.16 | 0.27 | |
Renal | 4 | 21 | 0.28 | Fixed | 1.37 | 0.92–2.04 | 0.12 | |
Renal in HWE | 2 | 0 | 0.64 | Fixed | 0.69 | 0.22–2.17 | 0.52 | |
TT+CT vs CC | Overall | 11 | 80 | 0.00 | Random | 1.10 | 0.83–1.45 | 0.52 |
Overall in HWE | 7 | 77 | 0.00 | Random | 1.20 | 0.88–1.64 | 0.25 | |
Caucasian | 5 | 89 | 0.00 | Random | 0.89 | 0.37–2.13 | 0.79 | |
Caucasian in HWE | 3 | 92 | 0.00 | Random | 1.61 | 0.61–4.25 | 0.34 | |
Asian | 3 | 0 | 0.86 | Fixed | 1.03 | 0.80–1.33 | 0.84 | |
Prostate | 6 | 87 | 0.00 | Random | 1.36 | 0.95–1.96 | 0.09 | |
Prostate in HWE | 4 | 87 | 0.00 | Random | 1.46 | 0.89–2.40 | 0.14 | |
Renal | 4 | 70 | 0.02 | Random | 0.62 | 0.33–1.19 | 0.15 | |
Renal in HWE | 2 | 29 | 0.23 | Fixed | 0.90 | 0.67–1.22 | 0.51 | |
T vs C | Overall | 11 | 78 | 0.00 | Random | 1.13 | 0.90–1.41 | 0.30 |
Overall in HWE | 7 | 75 | 0.00 | Random | 1.20 | 0.91–1.59 | 0.21 | |
Caucasian | 5 | 86 | 0.00 | Random | 1.17 | 0.68–2.00 | 0.57 | |
Caucasian in HWE | 3 | 92 | 0.00 | Random | 1.57 | 0.66–3.70 | 0.30 | |
Asian | 3 | 0 | 0.88 | Fixed | 1.05 | 0.82–1.35 | 0.68 | |
Prostate | 6 | 87 | 0.00 | Random | 1.35 | 0.96–1.89 | 0.08 | |
Prostate in HWE | 4 | 85 | 0.00 | Random | 1.43 | 0.93–2.21 | 0.10 | |
Renal | 4 | 44 | 0.15 | Fixed | 0.91 | 0.73–1.12 | 0.37 | |
Renal in HWE | 2 | 37 | 0.21 | Fixed | 0.89 | 0.67–1.19 | 0.43 |
HWE: Hardy-Weinberg Equilibrium.
The main results of meta-analysis about HIF1A A588T polymorphism were shown in
Genetic Model | Groups/Subgroups | Studies, n | Heterogeneity Test | Statistical Model | Test for Overall Effect | |||
OR | 95% CI | |||||||
AA+AG vs GG | Overall | 9 | 83 | 0.00 | Random | 1.40 | 0.76–2.58 | 0.28 |
Overall in HWE | 7 | 5 | 0.39 | Fixed | 1.13 | 0.89–1.44 | 0.32 | |
Caucasian | 4 | 87 | 0.00 | Random | 1.67 | 0.39–7.07 | 0.49 | |
Caucasian in HWE | 3 | 0 | 0.81 | Fixed | 0.82 | 0.41–1.62 | 0.56 | |
Asian | 3 | 53 | 0.12 | Fixed | 1.24 | 0.94–1.64 | 0.14 | |
Prostate | 4 | 0 | 0.50 | Fixed | 1.45 | 1.00–2.12 | ||
Prostate in HWE | 3 | 7 | 0.34 | Fixed | 1.44 | 0.98–2.10 | 0.06 | |
Renal | 4 | 92 | 0.00 | Random | 1.58 | 0.49–5.03 | 0.44 | |
Renal in HWE | 3 | 0 | 0.59 | Fixed | 1.04 | 0.71–1.51 | 0.85 | |
A vs G | Overall | 8 | 79 | 0.00 | Random | 1.57 | 0.89–2.76 | 0.12 |
Overall in HWE | 6 | 0 | 0.56 | Fixed | 1.24 | 0.96–1.62 | 0.10 | |
Caucasian | 4 | 81 | 0.00 | Random | 1.64 | 0.53–5.10 | 0.39 | |
Caucasian in HWE | 3 | 0 | 0.87 | Fixed | 0.92 | 0.48–1.78 | 0.81 | |
Asian | 2 | 35 | 0.22 | Fixed | 1.41 | 1.03–1.93 | ||
Prostate | 4 | 0 | 0.49 | Fixed | 1.46 | 1.01–2.12 | ||
Prostate in HWE | 3 | 10 | 0.33 | Fixed | 1.45 | 1.00–2.11 | ||
Renal | 4 | 89 | 0.00 | Random | 1.53 | 0.60–3.92 | 0.38 | |
Renal in HWE | 3 | 0 | 0.78 | Fixed | 1.07 | 0.74–1.55 | 0.71 |
HWE: Hardy-Weinberg Equilibrium.
Significant heterogeneity was observed in some comparisons (
The potential publication bias was firstly appraised by the funnel plot which showed no apparently asymmetric. Still, the results of Begg’s test revealed no publication bias (
Hypoxia is one of the fundamentally important features of solid tumors. Cellular response to hypoxia is partially governed by the activation of HIF1, which functions as a global regulator of oxygen homeostasis. HIF1 is a dimeric protein complex of α and β subunits, both of which are members of the basic helix-loop-helix Per/Arnt/Sim transcription factor family
Genetic differences are partly responsible for inter-individual diversity and variation in the development of complex diseases. SNP is one of the common genetic alterations, which serves as a new method for screening the etiology of cancer with complex inheritance
HIF1A A588T, also termed as Ala588Thr, G1790A, rs11549467, is located within the oxygen-dependent degradation domain (ODD) which spans from amino acid 401 to 603. In normoxia, HIF1A is hydroxylated on Pro402 and Pro564 followed by interaction with VHL to initiate rapid ubiquitination and proteasomal degradation. This may be one of the precise mechanisms that HIF1A A588T polymorphism plays its effect. In our study, the A allele was significantly correlated with higher urinary cancers risk in Asian population (OR = 1.41, 95% CI = 1.03–1.93,
HIF1A P582S, also termed as Pro582Ser, C1772T, rs11549465, is located in exon 12 near Pro564 within the ODD, which is supposed to affect the hydroxylation of Pro564 as HIF1A A588T. Additionally, this position is also located near the N-terminal transactivation domain (TAD-N), which spans from amino acid 531 to 575. Transcriptional activity of HIF-1 is facilitated by TAD-N and TAD-C in HIF1A and one another in HIF1B. In our study, individuals with TT genotype showed 1.60 fold higher risk than the other carrying CT or CC genotypes in Caucasian population (OR = 1.60, 95% CI = 1.09–2.33,
The current evidences suggest that HIF1A P582S polymorphism may correlate with urinary cancers risk in Caucasian population, while HIF1A A588T polymorphism increases the risk of urinary cancers in Asian population. Ethnicity may be an essential biological factor which influences HIF1A P582S and/or A588T polymorphisms through gene-gene interactions. As we presented in
Some studies reported that HIF1A P582S and A588T polymorphisms increased the risk of urinary cancers, while others failed to replicate the association between the two. The inconsistent results may largely derive from small sample size, different designed methods and complex genetic backgrounds. In our study, we conducted meta-analysis to get conclusions of higher statistical power. To our best knowledge, this is the first meta-analysis evaluating the association between HIF1A P582S and A588T polymorphisms and the susceptibility of urinary cancers. On the other hand, there were some limitations similar to other meta-analyses which might affected the final results of our study. We performed a systematic search to find as complete published case-control studies as possible. However, a few studies would not have been included in the meta-analysis. Also, the number of eligible studies as well as included cases and controls for some analyses was not large enough. Thereby, we were actually underpowered to get significant associations. Moreover, our final results were based on unadjusted estimates. A more precise analysis stratified by age, different gender, lifestyle, and stages/grades of cancers should be conducted as individual studies were available.
In the present study, we provide preliminarily genetic evidence that HIF1A P582S polymorphism is a potential factor for the susceptibility of urinary cancers in Caucasian population, while A588T polymorphism contributes to the risk of urinary cancers in Asian population and prostate cancer. Due to existing limitations, our conclusions should be interpreted with caution. Additional well-designed studies with larger sample size focusing on gene-gene and gene-environment are required to present robust evidence for the associations. Still, further molecular studies are warranted to clarify the effects of HIF1A P582S and A588T polymorphisms on the onset and progression of urinary cancers.
We thank Dr. Habuchi T for the availability to share data in the published paper.